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A study to assess the activity of tesevatinib in subjects with NSCLC and activating EGFR mutations who have disease progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who heave either BM or LM at initial presentation.

The primary objective is to evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating EGFR mutations and/or LM as measured by improvement in CTCAE v4.03 symptoms and signs (Cohort B)

Evaluate the activity of tesevatinib in subjects with NSCLC as measured by decreases in NSCLC cells in the CSF using standard cytology as assessed by the percent change in the number of NSCLC cells in the CSF for each patient in cohort B from screening to Cycle 1, Day 14, from Day 14 to Cycle 3, Day 1, and from screening to Cycle 3, Day 1 (Cohort B)

Evaluate the activity of tesevatinib in subjects with NSCLC as measured by changes in MRI findings consistent with leptomeningeal metastases (absent or present) for each patient in Cohort B from Cycle 1, Day 1 to Cycle 3, Day 1 and from Cycle 1, Day 1 to Cycle 5 Day 1 (Cohort B)

Pharmacokinetics [ Time Frame: 12 months ]

To evaluate the concentration of tesevatinib in CSF versus plasma (Cohort B)

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Ages Eligible for Study:

18 Years and older (Adult, Senior)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Cohort A

Inclusion Criteria:

History of NSCLC with EGFR mutation or an EGFR activating mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled.

Occurrence or progression of BM while receiving first line therapy (either erlotinib, afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If BM progression occurs after osimertinib, patient will be eligible.

At least one measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter). Target lesions must not have received stereotactic radiotherapy (SRS). If subject had prior whole brain radiotherapy (WBRT), progression in any measurable BM lesion must have occurred at least 3 months after the end of WBRT. Subjects with asymptomatic brain metastases may be enrolled without prior radiation therapy to the brain. Subjects with minimally symptomatic brain metastases may be enrolled without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant

Subjects in Cohort A may have asymptomatic LM detected by MRI. (Subjects with symptoms or signs attributed to LM will be enrolled in Cohort B whether or not they have brain metastases)

No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy

ECOG Score ≤2

No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not recurred

Adequate organ and bone marrow functions

Serum potassium and magnesium levels above the lower limit of normal

No coexisting medical problems of sufficient severity to limit compliance with the study

Willing and able to sign written informed consent and be able to comply with the study protocol for the duration of the study

Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test)

Exclusion Criteria:

First day of dosing with tesevatinib is less than 2 weeks from the last treatment of cytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks for nitrosoureas and mitomycin C. Surgical procedures must have been performed at least 2 weeks prior to the start of study treatment. Subjects must have recovered from the reversible effects of prior lung cancer treatments, including surgery and radiation therapy (excluding alopecia)

First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy of the brain or spinal cord/cauda equina

First day of dosing with tesevatinib is less than 2 weeks from treatment with another investigational agent

Treatment with erlotinib must be discontinued at least 3 days prior to first dose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must be discontinued at least 3 days prior to first dose of tesevatinib

Any concurrent therapy for BM other than the specified treatment in this study

Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine)

Taking any drugs associated with torsades de pointes or known to moderately or severely prolong the QTc(F) interval

History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be discussed with the medical monitor

Has an active infectious process

Female subject who is pregnant or lactating

Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body

Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470 msec) using the Fridericia method of correction for heart rate

Gastrointestinal (GI) condition that interferes with drug absorption

Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of brain metastases

Cohort B

Inclusion Criteria:

History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation) or, if previously treated, history of an activating EGFR mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled).

Presentation with LM at initial presentation with no prior systemic treatment, or occurrence or progression of LM while receiving first line therapy (either erlotinib, afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If LM progression occurs after osimertinib, patient will be eligible.

Presence of at least one CTCAE 4.03 symptom/sign of at least Grade 1 attributed by the investigator to leptomeningeal metastases

Diagnosis of LM by:

Cytological evidence in CSF sample of LM due to NSCLC, and/or

Findings on gadolinium-enhanced MRI

No clinically significant progression outside of the CNS on most recent EGFR inhibitor therapy

Concomitant brain metastases and brain metastases previously treated with radiation therapy are allowed. (Subjects with symptoms or signs attributed to LM will be enrolled in Cohort B whether or not they have brain metastases)

ECOG Score ≤2

No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not recurred.

Adequate organ and bone marrow functions

Serum potassium and magnesium levels above the lower limit of normal

No coexisting medical problems of sufficient severity to limit compliance with the study

Willing and able to sign written informed consent and be able to comply with the study protocol for the duration of the study

Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test)

Exclusion Criteria:

First day of dosing with tesevatinib is less than 2 weeks from the last treatment of cytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks for nitrosoureas and mitomycin C. Surgical procedures must have been performed at least 2 weeks prior to the start of study treatment. Subjects must have recovered from the reversible effects of prior lung cancer treatments, including surgery and radiation therapy (excluding alopecia)

First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy of the brain or spinal cord/cauda equina

First day of dosing with tesevatinib is less than 2 weeks from treatment with another investigational agent

Treatment with erlotinib must be discontinued at least 3 days prior to first dose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must be discontinued at least 3 days prior to first dose of tesevatinib

Any concurrent therapy for LM other than the specified treatment in this study

Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine)

Taking any drugs associated with torsades de pointes or known to moderately or severely prolong the QTc(F) interval

History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be discussed with the medical monitor

Has an active infectious process

Female subject who is pregnant or lactating

Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body

Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470 msec) using the Fridericia method of correction for heart rate

Gastrointestinal (GI) condition that interferes with drug absorption

Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of leptomeningeal metastases

Contraindications to lumbar puncture:

INR > 1.5

Platelets < 50 × 109/L (Note that platelets are required to be ≥100× 109/L at screening)

CNS lesions considered to be at risk for cerebral herniation, myelocompression, or conus/cauda compression

Cohort C

Inclusion Criteria:

NSCLC with EGFR activating mutation

No prior systemic treatment for NSCLC. Treatment with systemic steroids is not considered systemic treatment for NSCLC

No prior radiation therapy to the CNS (brain or spinal cord)

At least one measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter) in a subject with asymptomatic or minimally symptomatic brain metastases who does not require immediate surgical or radiation therapy in the opinion of the treating investigator and in the opinion of a radiation therapy or neurosurgical consultant.

Subjects in Cohort C may have asymptomatic LM detected by MRI

ECOG Score ≤2

No history of another malignancy in the 5 years prior to study entry, except treated non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and have not recurred

Adequate organ and bone marrow functions

Serum potassium and magnesium levels above the LLN

No coexisting medical problems of sufficient severity to limit compliance with the study.

Willing and able to sign written informed consent and be able to comply with the study protocol for the duration of the study

Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test)

Exclusion Criteria:

Surgical procedures that were performed less than 2 weeks prior to the start of study treatment

Any concurrent therapy for BM other than the specified treatment in this study

Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or any drugs that are CYP3A4 inducers (including anti-epileptic agents such as phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and fluoxetine)

Taking any drugs associated with torsades de pointes or known to moderately or severely prolong the QTc(F) interval

History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR interval only), or congenital long QT syndrome. Subjects with a history of atrial arrhythmias should be discussed with the medical monitor

Has an active infectious process

Female subject who is pregnant or lactating

Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body

Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F] interval > 470 msec) using the Fridericia method of correction for heart rate

GI condition that interferes with drug absorption

Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of brain metastases